Synthesis of hybrid phosphorated indenoquinolines and biological evaluation as topoisomerase I inhibitors and antiproliferative agents

Bioorg Med Chem Lett. 2022 Feb 1:57:128517. doi: 10.1016/j.bmcl.2021.128517.

María Fuertes ¹, Asier Selas ¹, Angela Trejo ¹, Birgitta R Knudsen ², Francisco Palacios ¹, Concepción Alonso ³

Affiliations

1 Departamento de Química Orgánica I, Facultad de Farmacia and Centro de Investigación Lascaray (Lascaray Research Center). Universidad del País Vasco/Euskal Herriko Unibertsitatea (UPV/EHU). Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain.
2 Department of Molecular Biology and Genetics and Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Aarhus 8000, Denmark.
3 Departamento de Química Orgánica I, Facultad de Farmacia and Centro de Investigación Lascaray (Lascaray Research Center). Universidad del País Vasco/Euskal Herriko Unibertsitatea (UPV/EHU). Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain. Electronic address: concepcion.alonso@ehu.eus.

PMID: 34952177 DOI: 10.1016/j.bmcl.2021.128517

Abstract

This work describes the first synthesis of diethyl 6,6a,7,11b-tetrahydro-5H-indeno[2,1-c]quinolinylphosphonates 5, diethyl 7H-indeno[2,1-c]quinolinylphosphonates 6 and diethyl 7-oxo-7H-indeno[2,1-c]quinolinylphosphonates 7, which were prepared in good to high overall yields. The synthetic route involves a multicomponent reaction of 2-phosphonateaniline, aldehydes and indene as olefin and allows the selective generation of three stereogenic centres in a short, efficient and reliable manner. The selective dehydrogenation of 1,2,3,4-tetrahydroindenoquinolines leads to the formation of corresponding indenoquinolines, and subsequent oxidation of methylene group of the indenoquinolines allows the access to indenoquinolinones.

Keywords

Antiproliferative effect; Enzyme inhibition; Indenoquinolinyl phosphonates; Topoisomerase I.

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